There is no established chemotherapy for anaplastic thyroid cancer. We conducted a prospective feasibility study at a single center to explore the antitumor activity of docetaxel against anaplastic thyroid cancer. Docetaxel was administered intravenously at a dose of 60 mg/m(2) over the course of 1 h every 3 weeks in patients with anaplastic thyroid cancer who had received no prior chemotherapy. A total of seven patients with anaplastic thyroid cancer were enrolled over the course of 30 months and received docetaxel. The treatment response was complete response in one patient, stable disease in two and progressive disease in four. The response rate was 14%, and the disease control rate (complete response plus stable disease) was 43%. The median time to progression was 6 weeks (range, 1-50). Toxicity was tolerable. Docetaxel could be an effective drug for the treatment of anaplastic thyroid cancer, with tolerable toxicity.

By performing hemodialysis 24 h after the start of chemotherapy, we obtained reproducible and robust AUC data. Use of the Calvert formula allowed carboplatin-based chemotherapy to be performed safely. Our results suggest that the non-renal clearance of carboplatin is lower in Japanese patients than in non-Asian patients.

No abstract

No abstract

Panobinostat (LBH589) is a potent pan-histone deacetylase inhibitor. As a result of promising preclinical data, Phase I and II clinical trials of intravenous and oral panobinostat have been conducted in patients with a wide variety of hematologic and solid tumors. This is the first report of a phase I study to evaluate intravenous panobinostat given on days 1 and 8 of a 21-day cycle in patients with solid tumors. The primary objective was to characterize the safety and tolerability of panobinostat by evaluating the occurrence of dose-limiting toxicity (DLT) and determining the maximum tolerated dose (MTD) in Japanese patients with advanced solid tumors. Secondary objectives included characterizing the pharmacokinetics and assessing antitumor activity. Fourteen patients were assigned to three dose levels (Cohort 1: 10 mg/m(2) [three patients], Cohort 2: 15 mg/m(2) [three patients], Cohort 3: 20 mg/m(2) [eight patients]), according to a standard "3 + 3" design. One patient who received 20 mg/m(2) had a DLT (grade 3 elevation of γ-glutamyl transpeptidase for >7 days). Thrombocytopenia was observed in all patients (grade 3 or 4 in 8), the severity of which was dependent on the dose and platelet count at baseline. The thrombocytopenia rapidly resolved within 8 days. Plasma panobinostat levels increased dose dependently, without clinically significant drug accumulation. Stable disease for ≥4 months was observed in six patients; however, there were no complete or partial responses. It is feasible to conclude that 20 mg/m(2) was the MTD and recommend as the starting dose for phase II clinical trials.

Objective: This pharmacokinetic study of S-1 was conducted in patients in whom glomerular filtration rate (GFR) was directly measured to explore the possibility of adjusting the S-1 dose on the basis of GFR in patients with normal or nearly normal renal function. Methods: S-1 was given to 12 patients twice daily for 28 consecutive days followed by 14 days of rest, repeated every 6 weeks. GFR was measured on the basis of inulin clearance (CLin) before the first day of treatment. Results: The area under the time-concentration curve (AUC) of 5-fluorouracil (5-FU) correlated with that of 5-chloro-2,4-dihydroxypyridine (CDHP, r = 0.750, p = 0.005). The AUC of CDHP correlated with the measured 24-hour creatinine clearance (CLcr) per subject (r = –0.620, p = 0.032), but not with the CLin (r = –0.356, p = 0.257). The AUC of 5-FU did not correlate with either the 24-hour CLcr per subject (r = –0.401, p = 0.187) or with the CLin (r = –0.300, p = 0.351). Conclusion: Dosage adjustment based on the GFR does not reduce individual variations in 5-FU concentrations among patients with normal or nearly normal renal function who receive S-1.

No abstract

Background: Signaling via the phosphatidylinositol 3-kinase (PI3K) pathway is critical to cancer cell growth, survival, and metabolism. BKM120 is a potent and highly specific oral pan-class I (α, β, γ, δ) PI3K inhibitor that has demonstrated clinical anti-tumor effects in a broad range of cancer types. Patients and methods: This was a phase I, open-label, dose-escalation study of single-agent BKM120 in Japanese patients with advanced solid tumors. Patients received 28-day cycles of continuous BKM120 once daily until disease progression, unacceptable toxicity, investigator's decision or patient's refusal. Eligible patients had histologically-confirmed, advanced unresectable solid tumors and had progressed on standard therapy, were unable to tolerate standard therapy, or had disease for which no standard therapy exists. Dose escalation, determined by agreement of investigators and the sponsor, was guided by an adaptive Bayesian logistic regression model with overdose control. Results: A total of 15 patients (median age 58 [range 22 to 71] yrs) received BKM120 once daily: 25 mg (n = 3), 50 mg (n = 3), and 100 mg (n = 9). The most common primary tumor sites were the salivary gland, rectum (n = 3 each), colon, and head & neck (n = 2 each). Patients were heavily pretreated (median 3 prior regimens [range 0–9]). One patient experienced a DLT (CTCAE grade 4 abnormal hepatic function at 100 mg BKM120 during cycle 1). Across all doses, the most common (≥ 4 patients) all-cause adverse events (AEs) were increased eosinophil count/eosinophilia, rash, increased blood insulin, constipation, decreased appetite, fatigue, increased alanine aminotransferase, anemia, increased insulin C-peptide, mood altered/psychiatric symptom, and pruritus. The most common (≥ 2 patients) non-dose limiting grade 3/4 AEs (all cause) were abnormal hepatic function (n = 5, including increased transaminase in 2 patients), and anemia (n = 2). Five patients experienced serious AEs (all cause): abnormal hepatic function (n = 3), pneumonitis, dyspnea, hyperglycemia, pneumonia, and delirium (n = 1 each). A patient with pneumonitis died 11 days after study drug discontinuation (100 mg cohort). There were 4 AE-associated discontinuations: 2 for increased transaminases (discontinuation on days 47 and 78 of treatment; 25 mg BKM120), 1 abnormal hepatic function (on day 30) and 1 increased lipase (on day 56; both 100 mg BKM120). Preliminary pharmacokinetic (PK) data showed rapid absorption, with Cmax occurring 1–3 hours post-dose. BKM120 accumulated ∼3-fold in achieving steady state. Doses ≥ 50 mg led to steady-state drug exposure (AUC0–24,ss) ≥ 10,000 ng*h/mL, a target preclinically estimated to be efficacious. Both Cmax and AUC increased dose proportionally between 25 and 100 mg. Five patients had stable disease (RECIST criteria) as the best response (8–24 weeks' duration). Based on the overall safety profile of BKM120, dose escalation over 100 mg was not pursued, and the recommended dose was declared as 100 mg once daily. Conclusions: BKM120 administered orally once daily up to 100 mg was well tolerated. PK parameters were comparable with those of Western patients. Continuous BKM120 100 mg once daily was recommended in Japanese patients and will be taken forward in the clinical development program. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B159.